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From Medscape Medical News

ICBD 2009: Abnormal Circadian Genes Implicated in Bipolar Disorder

Janis Kelly

July 7, 2009  Research using a new mouse model reported at the 8th International Conference on Bipolar Disorder, held in Pittsburgh, Pennsylvania, suggests that abnormalities in genes that control circadian rhythms contribute to the development of bipolar disorder.

"We have found that mice with a mutation in 1 of the core circadian genes, CLOCK, have a complete behavioral profile that is strikingly similar to human bipolar patients in the manic state. Furthermore, treatment with the mood stabilizer lithium restores their behavior to normal levels," reported Colleen A. McClung, PhD, assistant professor of psychiatry at the University of Texas Southwestern Medical Center, in Dallas.

Dr. McClung focused on genes that affect circadian rhythms because so many people with mood disorders have abnormal internal clocks. Depression and bipolar disorder are both associated with major disruptions in sleep and activity, and schedule changes can trigger episodes. Further, said Dr. McClung, polymorphisms in several circadian genes are linked to bipolar disorder, depression, and seasonal affective disorder in humans.

Many treatments for depression and bipolar disorder affect the circadian clock, such as bright light therapy, total sleep deprivation, phase advance shifts, social rhythm therapy, and melatonin therapy.

Dr. McClung studied the CLOCK-mutant mice because their behavior resembles that of bipolar patients in the manic state. Such patients are hyperactive, have a decreased need for sleep, report feelings of euphoria, become excessively involved in potentially painful activities, have a propensity toward drug use and abuse, and are likely to become obese.

The CLOCK-mutant mice are similarly hyperactive, sleep less than wild-type mice, are less depressed in behavioral models, have lowered anxiety and increased risky behavior in behavioral models, and are more sensitive to "rewards" of cocaine, sucrose, or brain stimulation. They also get fat.

Treating CLOCK-mutant mice with lithium returns activity to wild-type levels, as does viral expression of a functional CLOCK protein in the ventral tegmental area (VTA) of the midbrain, where neurons synthesize dopamine.

Dr. McClung said that the CLOCK mutation leads to an increase in dopaminergic activity in the VTA that is rescued by lithium treatment and that expression of a functional CLOCK protein specifically in the VTA rescues at least a portion of these maniclike responses. CLOCK regulates the expression in the VTA of several genes that control dopaminergic transmission.

"Our findings indicate a clear role for circadian genes (and the CLOCK gene in particular) in the control of mood, anxiety, and reward-related behavior," Dr. McClung told Medscape Psychiatry. "The CLOCK-mutant mice represent a very complete model of human mania, and their phenotypes are reversed by lithium treatment.

"This gives us a great opportunity to use this model to screen for drugs that might be effective antimanic agents, to discover the molecular and cellular mechanisms that underlie the development of mania, and to determine more specifically how lithium works as a therapeutic agent, since this is still unclear. These should all lead to more targeted and better treatments for at least the manic portion of bipolar disorder," she added.

John Kelsoe, MD, professor of psychiatry at the University of California, San Diego, who specializes in psychiatric genomics, told Medscape Psychiatry that research on polymorphisms in CLOCK genes are an important area for bipolar-disorder study.

"Patients with bipolar disorder have profound abnormalities in their circadian rhythms. Circadian rhythms are phase advanced in depression, and seasonal patterns are common in bipolar disorder. Sleep deprivation has an antidepressant effect. The problem is that the role of CLOCK genes in bipolar disorder is unknown.

"CLOCK genes have also been shown to play a role in response and sensitization to stimulants that are also a model of mania. Work to identify functional polymorphisms within CLOCK genes is certainly needed, as well as studies of CLOCK genes in bipolar subjects. These genes may well interact with other genes to produce illness with more circadian features," said Dr. Kelsoe.

The biological clock might also have diagnostic implications. But Paola Salvatore, MD, from Massachusetts General Hospital, in Belmont, who is studying circadian-rhythm abnormalities in ill and recovered bipolar-disorder patients, warned that more work is needed to determine whether a circadian disruption might be a biological marker and a trait of vulnerability and susceptibility to the illness.

"Basically, longitudinal studies on circadian rhythms both in patients during their euthymic phases and also among healthy first-degree relatives (children and siblings of bipolar-disorder patients) during their childhood and adolescence may shed some light on the mechanisms underlying this illness process," said Dr. Salvatore.

The authors report no conflict of interest.
8th International Conference on Bipolar Disorder: Abstract 4. Presented June 25, 2009.

Janis Kelly is a freelance writer for Medscape. She has been a medical journalist since 1976, with extensive work in rheumatology, immunology, neurology, sports medicine, AIDS and infectious diseases, oncology, and respiratory medicine.